Once considered a less serious form of bipolar (BP) I disorder, BP II disorder is now recognized as a distinct, prevalent illness associated with significant morbidity, psychosocial disability, and mortality. The depressive phase of the illness predominates and drives the morbidity associated with the disorder. At least 3 million individuals in the United States are affected, yet there are no established or approved treatments for this illness. In particular, little is known about the role of psychotherapy in the management of BP II disorder, an illness which is associated with significant psychosocial dysfunction and where, unlike BP I disorder, treatment with psychotherapy alone may, in some cases, suffice. Interpersonal and social rhythm therapy (IPSRT) is a manual-based psychotherapy that combines interpersonal psychotherapy (IPT) with a behaviorally based social rhythm therapy that teaches patients to regulate their daily activities. This well-studied treatment has documented efficacy (in combination with medication) for BP I disorder and preliminary data supporting its efficacy as monotherapy in BP II depression. The current application proposes a randomized, controlled trial comparing the efficacy of IPSRT alone to IPSRT plus medication for the treatment of BP II depression. An important innovation of the proposed trial is using as its base treatment a lower risk intervention (i.e., psychotherapy) in order to determine the incremental advantages of adding a higher risk intervention (i.e., medication). Specifically, we will enroll 160 individuals meeting DSM-IV criteria for BP II disorder, currently depressed, and randomly assign them to 20 weeks of treatment with IPSRT plus placebo (IPSRT-PLA) (N=80) or IPSRT plus quetiapine (IPSRT-QUE) (N=80). Primary outcomes are reductions in depressive symptoms, time to remission, and improvement in psychosocial functioning. An exploratory aim is to evaluate potential moderators of treatment outcomes including circadian phase preference, intercurrent hypomanic symptoms during the index depressive episode, epidemiologic and demographic factors (i.e., number of previous episodes, family history of mood disorders), and prior treatment response to antidepressant medications. Findings from this trial have the potential to inform treatment strategies for individuals suffering from BP II disorder, a neglected group with considerable mental health challenges whose improved outcomes would contribute to significant reductions in public health burden.